Jordi Casanova-Molla

On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies

&NA; This study analyzed the relationship between the density of intraepidermal nerve fibers (IENF) and the characteristics of either nociceptive laser‐evoked potentials (LEPs) or contact heat‐evoked potentials (CHEPs) in patients with painful sensory polyneuropathy with the aim to determine which parameters of LEPs and CHEPs more reliably reflect IENF loss. A total of 96 patients and 35 healthy volunteers took part in the study. Based on clinical examination, nerve conduction tests, and quantitative sensory testing, we identified 52 patients with small‐fiber neuropathy (SFN), 40 with mixed (small‐fiber and large‐fiber) neuropathy (MFN), and 4 who were excluded from the analysis because of no evidence of involvement of small fibers. The latency of the N2 was delayed for both LEPs and CHEPs in patients with MFN and for CHEPs only in patients with SFN. The amplitude of the vertex N2/P2 potential was similarly reduced in both types of neuropathy, but LEPs were more frequently absent than CHEPs in MFN patients (68% vs 40%). In general, latency and amplitude of LEPs and CHEPs were well correlated with IENF density. SFN patients were characterized by abnormal EPs and slightly decreased but morphologically abnormal IENF. MFN patients were characterized by frequently absent LEPs and CHEPs and a rather severe IENF loss. The correlation between nociceptive evoked potentials (laser‐evoked potentials and contact heat‐evoked potentials) and skin biopsy aids in the diagnosis of painful neuropathies.

C-nociceptors sensitized to cold in a patient with small-fiber neuropathy and cold allodynia

ABSTRACT Cold allodynia is a common sign of neuropathic pain patients but its underlying mechanisms are still largely unknown, partly because the populations of neurons responding to cold stimuli and their transduction mechanisms have not been fully determined. We report a patient with a small‐fiber neuropathy of unknown origin, whose main complaint is cold allodynia. Microneurographic recordings showed ongoing spontaneous activity and abnormal responses to cold and menthol in identified subtypes of C‐nociceptors. These findings provide the first direct evidence in human of abnormal peripheral nociceptor behavior potentially responsible for cold allodynia. The responsiveness of C‐nociceptors to menthol suggests an abnormal expression or function of TRPM8 channels in this patient with a small‐fiber polyneuropathy.

Influence of Corpus Callosum Damage on Cognition and Physical Disability in Multiple Sclerosis: A Multimodal Study

Background Corpus callosum (CC) is a common target for multiple sclerosis (MS) pathology. We investigated the influence of CC damage on physical disability and cognitive dysfunction using a multimodal approach. Methods Twenty-one relapsing-remitting MS patients and 13 healthy controls underwent structural MRI and diffusion tensor of the CC (fractional anisotropy; mean diffusivity, MD; radial diffusivity, RD; axial diffusivity). Interhemisferic transfer of motor inhibition was assessed by recording the ipsilateral silent period (iSP) to transcranial magnetic stimulation. We evaluated cognitive function using the Brief Repeatable Battery and physical disability using the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC) z-score. Results The iSP latency correlated with physical disability scores (r ranged from 0.596 to 0.657, P values from 0.004 to 0.001), and with results of visual memory (r = −0.645, P = 0.002), processing speed (r = −0.51, P = 0.018) and executive cognitive domain tests (r = −0.452, P = 0.039). The area of the rostrum correlated with the EDSS (r = −0.442, P = 0.045). MD and RD correlated with cognitive performance, mainly with results of visual and verbal memory tests (r ranged from −0.446 to −0.546, P values from 0.048 to 0.011). The iSP latency correlated with CC area (r = −0.345, P = 0.049), volume (r = −0.401, P = 0.002), MD (r = 0.404, P = 0.002) and RD (r = 0.415, P = 0.016). Conclusions We found evidence for structural and microstructural CC abnormalities associated with impairment of motor callosal inhibitory conduction in MS. CC damage may contribute to cognitive dysfunction and in less extent to physical disability likely through a disconnection mechanism.

Small fibre function in patients with meralgia paresthetica.

Introduction: Patients with meralgia paresthetica (MP) usually experience not only paraesthesias and decreased tactile sensation, but also painful dysesthesias in the distribution of the lateral femoral cutaneous nerve (LFCN). We aimed at assessing whether there is any functional impairment of small fibres of the LFCN in patients with MP. Methods: We carried out a clinical, psychophysical and neurophysiological study in 14 patients with MP and 14 healthy control subjects. We assessed pain in the last 2 months, thermal thresholds and small fibres conduction by using a visual analogue scale (VAS‐pain), quantitative sensory testing (QST) and contact heat‐evoked potentials (CHEPs), respectively. Data were grouped for control subjects, non‐affected side and affected side of patients with MP. Results: Patients marked a VAS‐pain of 4.3 ± 1.5. In the affected side, thresholds for warm and heat pain sensations were elevated and the amplitude of CHEPs was reduced in comparison to the non‐affected side and controls (Bonferroni’s test; p < 0.001 for all comparisons). The amplitude of CHEPs correlated inversely with duration of the symptoms (r = −0.57, p = 0.002), as well as with heat pain thresholds (r = −0.18, p = 0.01). No significant correlations were found between CHEPs and VAS‐pain (p > 0.05 for all correlations). Conclusion: Besides the involvement of large myelinated fibres, partial loss of function in small fibres may also account for the painful symptoms of patients with MP, especially in those with longer disease duration.

Epidermal Langerhans cells in small fiber neuropathies.

Summary Subjects with painful small fiber neuropathy, specially in the context of diabetics, had an increased number of the proinflammatory Langerhans cells at the skin. ABSTRACT We quantified the immune histiocytic Langerhans cells (LCs) in skin biopsy samples of patients with distal small fiber neuropathy (SFN). Patients were divided according to the presence or absence of neuropathic pain (burning pain) assessed by a visual analogue scale (VAS). We studied 13 diabetic patients (pain‐DSFN), 7 nondiabetic patients (pain‐SFN) who reported relevant neuropathic pain (VAS ⩾3), and 6 nondiabetic patients without neuropathic pain (no‐pain‐SFN). Using double immunofluorohistochemistry with the PGP 9.5 and the langerin/CD207, we quantified the intraepidermal nerve fibers density (IENFD) and LCs per square millimeter in the epidermis. A group of 10 skin samples from healthy subjects served as controls. Confocal analysis was performed to evaluate LC PGP 9.5‐immunoreactivity. We found a mean value of 334.3 LC/mm2 in controls, 310.2 LC/mm2 in no‐pain‐SFN, 329.6 LC/mm2 in pain‐SFN and 484.3 LC/mm2 in pain‐DSFN (analysis of variance; P = .01). In patients, analysis of covariance adjusted by different covariables showed that the presence of diabetes (F = 5.2, P = .03) was associated with an increased number of LC/mm2. There was a negative correlation between the IENFD and the number of LCs (r2 = −0.13, P = .03). No statistically significant differences were found among groups of subjects either for the co‐localization or for the number of LCs that were PGP 9.5‐immunoreactive (analysis of variance; P > .05). These results indicate that patients with neuropathic pain in the context of SFN, specially those who had diabetes (DSFN), had an increased number of LCs in the epidermis that may play a role in the generation or maintenance of neuropathic pain.

Clinical consequences of reinnervation disorders after focal peripheral nerve lesions

Axonal regeneration and organ reinnervation are the necessary steps for functional recovery after a nerve lesion. However, these processes are frequently accompanied by collateral events that may not be beneficial, such as: (1) Uncontrolled branching of growing axons at the lesion site. (2) Misdirection of axons and target organ reinnervation errors, (3) Enhancement of excitability of the parent neuron, and (4) Compensatory activity in non-damaged nerves. Each one of those possible problems or a combination of them can be the underlying pathophysiological mechanism for some clinical conditions seen as a consequence of a nerve lesion. Reinnervation-related motor disorders are more likely to occur with lesions affecting nerves which innervate muscles with antagonistic functions, such as the facial, the laryngeal and the ulnar nerves. Motor disorders are better demonstrated than sensory disturbances, which might follow similar patterns. In some instances, the available examination methods give only scarce evidence for the positive diagnosis of reinnervation-related disorders in humans and the diagnosis of such condition can only be based on clinical observation. Whatever the lesion, though, the restitution of complex functions such as fine motor control and sensory discrimination would require not only a successful regeneration process but also a central nervous system reorganization in order to integrate the newly formed peripheral nerve structure into the prepared motor programs and sensory patterns.

The somatosensory blink reflex in upper and lower brainstem lesions

The brainstem pathways that mediate the somatosensory blink reflex (SBR) are not completely understood. We hypothesized that the circuits of the SBR might be affected separately from those of the trigeminal blink reflex (TBR). We examined 7 patients with mesencephalic lesions and 8 patients with medullary lesions. The SBR was elicited by median nerve stimulation. The TBR was elicited by supraorbital nerve stimulation. In patients with upper brainstem lesions, the TBR was normal, whereas the SBR was generally abnormal. The SBR was either absent or small and was significantly delayed with respect to control subjects. The opposite was the rule in patients with lower brainstem lesions who had delayed or absent TBR and no abnormal findings in the SBR. The SBR is mediated through circuits in the upper brainstem. Study of the SBR can be helpful in the neurophysiological assessment of patients with mesencephalic lesions. Muscle Nerve 43: 196–202, 2011

Mitochondrial loss indicates early axonal damage in small fiber neuropathies

Evaluation of nerve fibers in the skin provides a useful tool for the diagnosis of small fiber neuropathies (SFNs). Our aim was to determine whether mitochondria are involved in SFN, indicating early axonal damage. We quantified mitochondrial respiratory chain complex IV (OXPHOS) and axonal (PGP 9.5) fluorescence on skin sections from 32 SFN patients and 14 healthy controls. Also, a group of six patients were recruited before and after 30‐day treatment with the mitotoxic antibiotic linezolid. We measured the co‐localization of OXPHOS within the intraepidermal and subpapillary dermal axons (PGP‐immunoreactive [PGP‐ir]). SFN patients with relatively preserved intraepidermal nerve fibers (SFN borderline) showed statistically significant reduction of OXPHOS (50.5 ± 33.9 µm2 vs. 107.6 ± 81 µm2 in controls, p < 0.02). A positive correlation was found between both PGP‐ir and OXPHOS in controls (Pearsons coefficient r = 0.59, p < 0.001), whereas such correlation was absent in SFN. With respect to baseline measurements, linezolid therapy increased both PGP‐ir and OXPHOS, which could be considered an initial compensatory toxic‐induced response. This study set out to identify a possible marker of axonal pre‐degenerative state in SFN borderline patients.

Transient decrease of sensory perception after thermoalgesic stimuli for quantitative sensory testing.

Transient decrease in the excitability of a reflex circuit following its activation by appropriate stimuli is a well‐recognized phenomenon, but it is unclear how this applies to thermoalgesic stimuli during quantitative sensory testing (QST). We examined the effects induced by a thermoalgesic (conditioning) stimulus on the response to a subsequent (test) stimulus of the same characteristics. All tests were done using a Peltier thermode with a surface area of 12.5 cm2 using ramp rates of 2°C/s and variable interstimulus intervals (ISIs) ranging from 10 to 60 s. Perception was measured with an electronic visual analog scale. No changes were observed in latency of pain perception. However, latency of warm perception was significantly delayed and pain perception intensity was significantly reduced with respect to conditioning stimuli at ISIs below 60 s. Our results indicate a transient saturation of warm and heat pain perception systems after a thermoalgesic stimulus. We therefore recommend that time intervals of >1 min be used between two consecutive thermoalgesic stimuli when examining QST. Muscle Nerve, 2007

Axonal fluorescence quantitation provides a new approach to assess cutaneous innervation.

We present a novel approach to quantify skin innervation by measuring the PGP 9.5 immunoreactive (PGP-ir) fluorescence corresponding to axons within the epidermis and dermis. The skin biopsies from 35 controls and 45 small fiber neuropathy (SFN) patients were included. In 50-μm free-floating sections, we determined the intraepidermal nerve fiber density (IENFD) by direct fluorescence visualization and captured 2-μm thick individual optical sections using the same confocal microscope and magnification. We measured the fluorescence of the PGP-ir axons in both, epidermal and dermal area by using the ImageJ software. There was good interobserver and intraobserver reliability of PGP-ir measures, similar than for IENFD. The PGP-ir axons were found decreased in patients with SFN (1.1‰ and 9.0‰ respectively for epidermal and dermal area in contrast to 2.2‰ and 16.0‰, respectively to controls). The area under the ROC curve was 0.90 for the IENFD, 0.84 for epidermal PGP-ir axons and 0.70 for dermal PGP-ir axons. There was a positive correlation between the IENFD and the PGP-ir axons at epidermis (Spearman Rho=0.66, p<0.001) as well as for the dermal nerve length and the PGP-ir axons at dermis (Spearman Rho=0.45, p<0.05). This method is also particularly adequate for the quantitation of dermal nerve fibers. We conclude that quantifying the fluorescent PGP-ir axons could help to assess skin innervation (dermal and epidermal nerve fibers) in patients with SFN.